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Published December 2005 | public
Journal Article

Regulation of spinophilin Ser94 phosphorylation in neostriatal neurons involves both DARPP-32-dependent and independent pathways

Abstract

Spinophilin is a protein phosphatase-1 (PP-1)- and actin-binding protein that is enriched in dendritic spines. Phosphorylation of the actin-binding domain of rat spinophilin at one or more sites by protein kinase A (PKA) inhibits actin binding. Here, we investigated the regulation of mouse spinophilin that contains only a single PKA-site (Ser94) within its actin-binding domain. In vitro phosphorylation of Ser94 resulted in the dissociation of spinophilin from actin filaments. In mouse neostriatal slices, phospho-Ser94 (p-Ser94) was dephosphorylated mainly by PP-1 and also by PP-2A. Activation of dopamine D1 receptors in striatonigral medium spiny neurons, and of adenosine A2A receptors in striatopallidal medium spiny neurons increased, whereas activation of dopamine D2 receptors in striatopallidal neurons decreased, spinophilin Ser94 phosphorylation. In neostriatal slices from DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) knockout mice, the effects of D1, D2 and A2A receptors were largely attenuated. Activation of NMDA receptors decreased Ser94 phosphorylation in a PP-2A-dependent, but DARPP-32-independent, manner. These results suggest that PKA-dependent phosphorylation of spinophilin at Ser94 in both striatonigral and striatopallidal neurons requires synergistic contributions from the PKA and DARPP-32/PP-1 pathways. In addition, PP-2A plays a role in Ser94 dephosphorylation in response to activation of both D2 and NMDA receptors.

Additional Information

© 2005 International Society for Neurochemistry. Issue published online: 21 NOV 2005; Article first published online: 21 NOV 2005; Received June 24, 2005; revised manuscript received August 9, 2005; accepted August 10, 2005. We thank Patrick B. Allen (Yale University School of Medicine, New Heaven, CT, USA) for providing the spinophilin antibody, and Yukako Terasaki, Keiko Fujisaki and Michiko Koga for excellent technical assistance. This research was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (to AN) and grants from the USPHS (MH40899 and DA10044 to ACN and PG).

Additional details

Created:
August 22, 2023
Modified:
October 23, 2023